tbuckley/cabot-search huggingface dataset:
MMP9 Clears the Way for Metastatic Cell Penetration Across the Blood–Brain Barrier
Authors: Joseph H. McCarty
Journal: Cancer Research (2023)

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence microcopy and serial reconstruction of ultrastructural sections to analyze BBB breach and subsequent colonization of the brain. They show that matrix metalloprotease 9 (MMP9) plays a central role in these events. Pharmacologic or genetic targeting of MMP9 significantly reduced penetration across the BBB and limited micrometastasis formation. Surprisingly, extravasation and brain colonization does not involve significant degradation of canonical MMP9 protein targets such as collagen and laminin in vascular basement membranes, indicating the requirement for other extracellular matrix (ECM) or non-ECM substrates for MMP9. Collectively, these new and important findings reveal cell-cell adhesion and signaling events between cerebral endothelial and metastatic cancer cells as well as identify potential therapeutic targets to prevent metastatic tumor cell dissemination in the brain. See related article by Karreman et al., p. 1299.
A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design
Authors: Srona Sengupta, Josephine Zhang, Madison C. Reed, Jeanna Yu, Aeryon Kim, Tatiana N. Boronina, Nathan L. Board, James O. Wrabl, Kevin Shenderov, Robin A. Welsh, Weiming Yang, Andrew E. Timmons, Rebecca Hoh, Robert N. Cole, Steven G. Deeks, Janet D. Siliciano, Robert F. Siliciano, Scheherazade Sadegh-Nasseri
Journal: The Journal of Experimental Medicine (2023)

Distinct CD4+ T cell epitopes have been associated with spontaneous control of HIV-1 replication, but analysis of antigen-dependent factors that influence epitope selection is lacking. To examine these factors, we used a cell-free antigen processing system that incorporates soluble HLA-DR (DR1), HLA-DM (DM), cathepsins, and full-length protein antigens for epitope identification by LC-MS/MS. HIV-1 Gag, Pol, Env, Vif, Tat, Rev, and Nef were examined using this system. We identified 35 novel epitopes, including glycopeptides. Epitopes from smaller HIV-1 proteins mapped to regions of low protein stability and higher solvent accessibility. HIV-1 antigens associated with limited CD4+ T cell responses were processed efficiently, while some protective epitopes were inefficiently processed. 55% of epitopes obtained from cell-free processing induced memory CD4+ T cell responses in HIV-1+ donors, including eight of 19 novel epitopes tested. Thus, an in vitro processing system utilizing the components of Class II processing reveals factors influencing epitope selection of HIV-1 and represents an approach to understanding epitope selection from non-HIV-1 antigens.
Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases
Authors: Colin S. Wood, Kathryn A.F. Pennel, Holly Leslie, Assya Legrini, Andrew J. Cameron, Lydia Melissourgou-Syka, Jean A. Quinn, Hester C. van Wyk, Jennifer Hay, Antonia K. Roseweir, Colin Nixon, Campbell S.D. Roxburgh, Donald C. McMillan, Andrew V. Biankin, Owen J. Sansom, Paul G. Horgan, Joanne Edwards, Colin W. Steele, Nigel B. Jamieson
Journal: Cancer Research (2023)

Abstract Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFβ signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Significance: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.
BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality
Authors: Junko Murai, Yves Pommier
Journal: Cancer Research (2023)

The concept of "BRCAness" was first described in 2004 to define the situation in which a homologous recombination repair (HRR) defect in a tumor relates to and phenocopies BRCA1 or BRCA2 loss-of-function mutations. Soon after the discovery of synthetic lethality of PARP1/2 inhibitors in BRCA1- or BRCA2-deficient cells, McCabe and colleagues extended the concept of BRCAness to homologous recombination deficiency (HRD) by studying the sensitivity of cancer cells to PARP inhibitors. They genetically revealed that deficiency in HR-related genes (RAD51, RAD54, DSS1, and RPA1), DNA damage signaling genes (ATR, ATM, CHK1, CHK2, and NBS1), or Fanconi anemia-related genes (FANCD2, FANCA, and FANCC) conferred sensitivity to PARP inhibitors. Thus, cells acquire BRCAness either by genetic inactivation of the BRCA or HRD genes. Here, we briefly review how genomic profiling can identify BRCAness and deficiencies in HRD genes and the current difficulty to apply BRCAness/HRD in the clinic. We also discuss how BRCAness relates to HRD and the utility of evaluating BRCAness/HRD to select therapies with PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib, pamiparib, fuzuloparib), topoisomerase I (TOP1) inhibitors (irinotecan, topotecan, and tumor-targeted TOP1 inhibitors), and platinum derivatives (cisplatin and carboplatin). See related article by McCabe and colleagues, Cancer Res 2006;66:8109-15.
Indication of Activated Senescence Pathways in the Temporal Arteries of Patients With Giant Cell Arteritis
Authors: William F. Jiemy, Yannick van Sleen, Jacoba C. Graver, Sarah Pringle, Elisabeth Brouwer, K. S. M. van der Geest, Divi Cornec, Annemieke M. H. Boots, Maria Sandovici
Journal: Arthritis & Rheumatology (2023)

Giant cell arteritis (GCA) affects almost exclusively individuals above 50 years old, suggesting a role of aging-related changes such as cellular senescence in its pathobiology. The kinases p21(WAF1/CIP1) and p16/INK4A play key roles in 2 distinct pathways leading to senescence. The proinflammatory molecules interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are key components of the senescence-associated secretory phenotype (SASP), are effective targets of treatment in GCA. Here, we aimed to investigate the presence of p21+ and p16+ cells producing these SASP cytokines in temporal artery biopsies (TABs) of patients with GCA.Eight patients with GCA and 14 age-matched, non-GCA individuals who underwent a TAB were included. Immunohistochemical staining of p21, p16, IL-6, and GM-CSF was performed. Multiplex immunofluorescent staining was performed to investigate the colocalization of p21 and p16 with IL-6, GM-CSF, and immune cell markers (CD68, CD3, CD20).We found that expression levels of p16, p21, IL-6, and GM-CSF were elevated in the TABs of patients with GCA. Both p16- and p21-expressing cells were mainly found near the internal lamina elastica, especially among giant cells and macrophages, although p21 and p16 expression could be found in all 3 layers of the vessels. Expression of p16 and p21 was occasionally found in T cells but not B cells. The p16+ and p21+ cells expressing GM-CSF/IL-6 were detected throughout the TABs.Our data suggest the presence of activated senescence pathways at the site of vascular inflammation in GCA and support further research into the role of senescence in the pathophysiology of GCA.
Associations between Aircraft Noise Exposure and Self-Reported Sleep Duration and Quality in the United States-Based Prospective Nurses’ Health Study Cohort
Authors: Matthew Bozigar, Tianyi Huang, Susan Redline, Jaime E. Hart, Stephanie T. Grady, Daniel D. Nguyen, Peter James, Bradley Nicholas, Jonathan I. Levy, Francine Laden, Junenette L. Peters
Journal: Environmental Health Perspectives (2023)

Background: Sleep disruption is linked with chronic disease, and aircraft noise can disrupt sleep. However, there are few investigations of aircraft noise and sleep in large cohorts. Objectives: We examined associations between aircraft noise and self-reported sleep duration and quality in the Nurses' Health Study, a large prospective cohort. Methods: Aircraft nighttime equivalent sound levels (Lnight) and day–night average sound levels (DNL) were modeled around 90 U.S. airports from 1995 to 2015 in 5-y intervals using the Aviation Environmental Design Tool and linked to geocoded participant residential addresses. Lnight exposure was dichotomized at the lowest modeled level of 45 A-weighted decibels [dB(A)] and at multiple cut points for DNL. Multiple categories of both metrics were compared with <45 dB(A). Self-reported short sleep duration (<7 h/24-h day) was ascertained in 2000, 2002, 2008, 2012, and 2014, and poor sleep quality (frequent trouble falling/staying asleep) was ascertained in 2000. We analyzed repeated sleep duration measures using generalized estimating equations and sleep quality by conditional logistic regression. We adjusted for participant-level demographics, behaviors, comorbidities, and environmental exposures (greenness and light at night) and examined effect modification. Results: In 35,226 female nurses averaging 66.1 years of age at baseline, prevalence of short sleep duration and poor sleep quality were 29.6% and 13.1%, respectively. In multivariable models, exposure to Lnight ≥45 dB(A) was associated with 23% [95% confidence interval (CI): 7%, 40%] greater odds of short sleep duration but was not associated with poor sleep quality (9% lower odds; 95% CI: −30%, 19%). Increasing categories of Lnight and DNL ≥45 dB(A) suggested an exposure–response relationship for short sleep duration. We observed higher magnitude associations among participants living in the West, near major cargo airports, and near water-adjacent airports and among those reporting no hearing loss. Discussion: Aircraft noise was associated with short sleep duration in female nurses, modified by individual and airport characteristics. https://doi.org/10.1289/EHP10959
Dendrimer-enabled targeted delivery attenuates glutamate excitotoxicity and improves motor function in a rabbit model of cerebral palsy
Authors: Fan Zhang, Zhi Zhang, Jesse Alt, Siva P. Kambhampati, Anjali Sharma, Sarabdeep Singh, Elizabeth Nance, Ajit G. Thomas, Camilo Rojas, Rana Rais, Barbara S. Slusher, Rangaramanujam M. Kannan, Sujatha Kannan
Journal: Journal of Controlled Release (2023)
Aligned ice Templated Biomaterial Strategies for the Musculoskeletal System
Authors: Florencia Diaz, Nicholas Forsyth, Aldo R. Boccaccini
Journal: Advanced Healthcare Materials (2023)

Abstract Aligned pore structures present many advantages when conceiving biomaterial strategies for treatment of musculoskeletal disorders. Aligned ice templating (AIT) is one of the many different techniques capable of producing anisotropic porous scaffolds; its high versatility allows for the formation of structures with tunable pore sizes, as well as the use of many different materials. AIT has been found to yield improved compressive properties for bone tissue engineering (BTE), as well as higher tensile strength and optimized cellular alignment and proliferation in tendon and muscle repair applications. This review evaluates the work that has been done in the last decade toward the production of aligned pore structures by AIT with an outlook on the musculoskeletal system. This work describes the fundamentals of the AIT technique and focuses on the research carried out to optimize the biomechanical properties of scaffolds by modifying the pore structure, categorizing by material type and application. Related topics including growth factor incorporation into AIT scaffolds, drug delivery applications, and studies about immune system response will be discussed.
When I use a word . . . Medical definitions: Pharmacovigilance
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Based on its etymology, previous definitions, and an examination of the practical processes involved, I suggest the following extensional definition of pharmacovigilance: <b>pharmacovigilance</b>, <i>n</i>. A scientific surveillance activity that can be carried out both before and after marketing of a medicinal or other therapeutic product, involving identification and quantification of signals that suggest the occurrence of previously unrecognised harms and their dose-responsiveness and time course, identification and refutation of false-positive signals that thus arise, elucidation of a product’s pharmacological and toxicological properties and the relevant mechanism(s) that mediate benefits and harms, identification of factors that contribute to the risks of harms, including the method of administration and factors that render subgroups of patients at particular risk (i.e. susceptible individuals), description of the comparative adverse effects profile of products within the same therapeutic class, continued surveillance of a product throughout the duration of its use, detection of medication errors and their sources, detection of clinically important interactions with other therapeutic or diagnostic products, and communication of appropriate information to healthcare professionals and the public. [ancient Greek ϕαρμακο-, combining form, from ϕάρμακον drug, medicine, poison, and Latin <i>vigilare</i> to be watchful or alert, via French <i>vigilance</i>.]
Hybrid Cell Membrane‐Functionalized Matrixes for Modulating Inflammatory Microenvironment and Improving Bone Defect Repair
Authors: Fangyu Qiao, Yonggang Lv
Journal: Advanced Healthcare Materials (2023)

Cell membranes from different sources retain the integrity of the original membrane structure and special membrane protein functions. However, the diversity function of membrane surface proteins is underutilized in bone defect repair. The current study creatively prepared a hybrid membrane (HM) (diameter, 92.25 ± 16.47 nm) and coated it on a poly-ε-caprolactone (PCL) (diameter, 313.79 ± 4.69 nm) electrospinning membrane for cell membrane-functionalized matrixes (MFMs) (diameter, 368.76 ± 5.90 nm) preparation. The effects of the HM and MFMs on inflammatory regulation and bone formation are further explored in vitro and in vivo. The results showed that MFMs can regulate macrophage into anti-inflammatory phenotype and promote alkaline phosphatase secretion and mineralization deposition of mesenchymal stem cells (MSCs) in vitro. The foreign body response is alleviated and bone regeneration is facilitated in rat calvarial critical-size defect in vivo. The study provides an innovative approach to applicate the cell membrane functions from different sources for immunomodulatory and osteogenic differentiation and provides a promising choice for designing bone repair materials.
Enhanced nuclear translation is associated with proliferation and progression across multiple cancers
Authors: Sailan Zou, Byung‐Wook Kim, Yan Tian, Geng Liu, Jiawei Zhang, Ricardo Zerda, Zhuo Li, Guixiang Zhang, Xiao Du, Weiqiang Lin, Xiang Gao, Wendong Huang, Xianghui Fu
Journal: MedComm (2023)

Recent technological advances have re-invigorated the interest in nuclear translation (NT), but the underlying mechanisms and functional implications of NT remain unknown. Here we show that NT is enhanced in malignant cancer cells and is associated with rapid cell growth. Nuclear ribopuromycylation analyses in a panel of diverse cell lines revealed that NT is scarce in normal immortalized cells, but is ubiquitous and robust in malignant cancer cells. Moreover, NT occurs in the nucleolus and requires normal nucleolar function. Intriguingly, NT is reduced by cellular stresses and anti-tumor agents and positively correlates with cancer cell proliferation and growth. By using a modified puromycin-associated nascent chain proteomics, we further identified numerous oncoproteins that are preferentially translated in the nucleus, such as transforming growth factor-beta 2 (TGFB2) and nucleophosmin 1 (NMP1). Specific overexpression of TGFB2 and NMP1 messenger RNAs in the nucleus can increase their protein levels and promote tumorigenesis. These findings establish a previously unknown link between NT and malignancy and suggest that cancer cells might have adapted a mechanism of NT to support their need for rapid growth, which highlight the potential of NT in tumorigenesis and might also open up new possibilities for therapeutic targeting of cancer-specific cellular functions.
Real-Time Fluorescence Imaging to Identify Cholangiocarcinoma in the Extrahepatic Biliary Tree Using an Enzyme-Activatable Probe
Authors: Ryugen Takahashi, Takeaki Ishizawa, Yoshinori Inagaki, Mariko Tanaka, Akira Ogasawara, Yugo Kuriki, Kyohhei Fujita, Mako Kamiya, Tetsuo Ushiku, Yasuteru Urano, Kiyoshi Hasegawa
Journal: Liver Cancer (2023)

Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme.Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues.Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of 7 patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in 4 patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA.Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.
Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775
Authors: Vicky Makker, Nicoletta Colombo, Antonio Casado Herráez, Bradley J. Monk, Helen Mackay, Alessandro D. Santin, David S. Miller, Richard G. Moore, Sally Baron-Hay, Isabelle Ray-Coquard, Kimio Ushijima, Kan Yonemori, Yong Man Kim, Eva M. Guerra Alia, Ulus A. Sanli, Steven Bird, Robert Orlowski, Jodi McKenzie, Chinyere Okpara, Gianmaria Barresi, Domenica Lorusso
Journal: Journal of Clinical Oncology (2023)

JCO
Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238
Authors: James Larkin, Michele Del Vecchio, Mario Mandalá, Helen Gogas, Ana M. Arance Fernandez, Stéphane Dalle, Charles Lance Cowey, Michael Schenker, Jean-Jacques Grob, Vanna Chiarion-Sileni, Ivan Marquez-Rodas, Marcus O. Butler, Anna Maria Di Giacomo, Mark R. Middleton, Jose Lutzky, Luis de la Cruz-Merino, Petr Arenberger, Victoria Atkinson, Andrew G. Hill, Leslie A. Fecher, Michael Millward, Paul D. Nathan, Nikhil I. Khushalani, Paola Queirolo, Corey Ritchings, Maurice Lobo, Margarita Askelson, Hao Tang, Sonia Dolfi, Paolo A. Ascierto, Jeffrey Weber
Journal: Clinical Cancer Research (2023)

In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.